Combined quantum mechanics/molecular mechanics (QM/MM) Monte Carlo free energy simulations: a feasibility study
Lead Research Organisation:
University of Bristol
Department Name: Chemistry
Abstract
Despite the advances of science, millions of people still die every year from incurable diseases. Unfortunately, the costs of drug development are so high that the focus of medicinal research is into profitable Western diseases. To reduce the costs of developing new medicinal drugs, we would like to be able to use computers to model how a potential drug works within the body, and to use this knowledge to design new and better drugs. Building computational models like this is challenging, requiring a delicate balance between putting enough detail into the model to get realistic behaviour, and making the model as simple as possible so that it doesn't take too long to run the calculations. Until now, the majority of models used have been very simple, modelling the atoms of a drug as balls on springs. By treating the atoms as solid balls, the models neglect the atom's most chemically important part, namely the electrons. This is a severe oversight, as it is the interactions of electrons that determine whether the drug could dissolve in your blood, work its way into your cells, and bind to, and thus neutralize, the proteins of any attacking bacteria or virus. It is possible to model electrons in molecules using quantum mechanics. However, to model the entire protein/drug system using quantum mechanics would be too computationally expensive. We propose to research the use of quantum mechanics to model just the electrons that are part of, and near to, the drug molecule. The rest of the protein can still be treated by simple ball and springs models to make the calculations possible. The new methods we will develop add important extra detail, making them more realistic and better able to model how drugs interact. At the same time, this combined approach should mean that the calculations are practical to do. What makes our planned work different is that it will involve the development of a mixed model specifically tailored for medicinal drug design. Creating a mixed model for this use will require that significant challenges are overcome, and that new ways are developed to handle the interactions between the quantum mechanics part of the model with the ball on springs part.
Organisations
Publications
Çinaroglu SS
(2021)
Evaluating the Performance of Water Models with Host-Guest Force Fields in Binding Enthalpy Calculations for Cucurbit[7]uril-Guest Systems.
in The journal of physical chemistry. B
Çinaroglu S
(2023)
Computed Protein-Protein Enthalpy Signatures as a Tool for Identifying Conformation Sampling Problems
in Journal of Chemical Information and Modeling
Zurek J
(2004)
MM and QM/MM Modeling of Threonyl-tRNA Synthetase: Model Testing and Simulations
in Structural Chemistry
Zinovjev K
(2020)
Enlighten2: molecular dynamics simulations of protein-ligand systems made accessible.
in Bioinformatics (Oxford, England)
Zhang X
(2018)
Multiscale analysis of enantioselectivity in enzyme-catalysed 'lethal synthesis' using projector-based embedding.
in Royal Society open science
Yang Z
(2021)
Multiscale Workflow for Modeling Ligand Complexes of Zinc Metalloproteins.
in Journal of chemical information and modeling
Yamamoto E
(2020)
Multiple lipid binding sites determine the affinity of PH domains for phosphoinositide-containing membranes.
in Science advances
Wu Z
(2019)
Proton Control of Transitions in an Amino Acid Transporter.
in Biophysical journal
Woods CJ
(2013)
Computational assay of H7N9 influenza neuraminidase reveals R292K mutation reduces drug binding affinity.
in Scientific reports
Woods CJ
(2015)
Combined quantum mechanics/molecular mechanics (QM/MM) simulations for protein-ligand complexes: free energies of binding of water molecules in influenza neuraminidase.
in The journal of physical chemistry. B
Woods CJ
(2009)
Multicore Parallelization of Kohn-Sham Theory.
in Journal of chemical theory and computation
Woods CJ
(2008)
An efficient method for the calculation of quantum mechanics/molecular mechanics free energies.
in The Journal of chemical physics
Woods CJ
(2011)
A water-swap reaction coordinate for the calculation of absolute protein-ligand binding free energies.
in The Journal of chemical physics
Woods CJ
(2014)
Rapid decomposition and visualisation of protein-ligand binding free energies by residue and by water.
in Faraday discussions
Woods CJ
(2024)
Sire: An interoperability engine for prototyping algorithms and exchanging information between molecular simulation programs.
in The Journal of chemical physics
Woods C
(2008)
Chemical Modelling - Applications and Theory
Winokan M
(2023)
Multiscale simulations reveal the role of PcrA helicase in protecting against spontaneous point mutations in DNA.
in Scientific reports
Wells SA
(2015)
Structure and Function in Homodimeric Enzymes: Simulations of Cooperative and Independent Functional Motions.
in PloS one
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(2017)
Construction and in vivo assembly of a catalytically proficient and hyperthermostable de novo enzyme.
in Nature communications
Warman H
(2023)
How proton transfer impacts hachimoji DNA.
in RSC advances
Wang L
(2020)
Mixing and matching genes of marine and terrestrial origin in the biosynthesis of the mupirocin antibiotics.
in Chemical science
Walters RK
(2022)
The emerging potential of interactive virtual reality in drug discovery.
in Expert opinion on drug discovery
Walker EJ
(2024)
Cooperative Conformational Transitions Underpin the Activation Heat Capacity in the Temperature Dependence of Enzyme Catalysis.
in ACS catalysis
Von Kügelgen A
(2020)
In Situ Structure of an Intact Lipopolysaccharide-Bound Bacterial Surface Layer.
in Cell
Von Kügelgen A
(2024)
Membraneless channels sieve cations in ammonia-oxidizing marine archaea
in Nature
Von Glehn Patrick
(2015)
Modelling the reactivity of glutamate mutase and heme dioxygenase enzymes
Voice AT
(2021)
Mechanism of covalent binding of ibrutinib to Bruton's tyrosine kinase revealed by QM/MM calculations.
in Chemical science
Voice Angus
(2021)
Modelling the reactivity of cysteine targeting covalent inhibitors
Voice A
(2019)
Limitations of Ligand-Only Approaches for Predicting the Reactivity of Covalent Inhibitors.
in Journal of chemical information and modeling
Vinas Teresa Minguez
(2021)
A Conserved Arginine with Non-Conserved Function is a Key Determinant of Agonist Selectivity in Alpha7 Nicotinic Acetylcholine Receptors
in BIOPHYSICAL JOURNAL
Van Der Kamp MW
(2013)
Conformational change and ligand binding in the aristolochene synthase catalytic cycle.
in Biochemistry
Van Der Kamp MW
(2008)
Biomolecular simulation and modelling: status, progress and prospects.
in Journal of the Royal Society, Interface
Van Der Kamp MW
(2010)
Testing high-level QM/MM methods for modeling enzyme reactions: acetyl-CoA deprotonation in citrate synthase.
in The journal of physical chemistry. B
Van Der Kamp MW
(2007)
Ab initio QM/MM modelling of acetyl-CoA deprotonation in the enzyme citrate synthase.
in Journal of molecular graphics & modelling
Van Der Kamp MW
(2018)
Dynamical origins of heat capacity changes in enzyme-catalysed reactions.
in Nature communications
Van Der Kamp MW
(2008)
High-level QM/MM modelling predicts an arginine as the acid in the condensation reaction catalysed by citrate synthase.
in Chemical communications (Cambridge, England)
Van Der Kamp MW
(2011)
"Lethal synthesis" of fluorocitrate by citrate synthase explained through QM/MM modeling.
in Angewandte Chemie (International ed. in English)
Van Der Kamp MW
(2013)
Combined quantum mechanics/molecular mechanics (QM/MM) methods in computational enzymology.
in Biochemistry
Van Der Kamp MW
(2008)
Computational enzymology: insight into biological catalysts from modelling.
in Natural product reports
Van Der Kamp M
(2009)
ChemInform Abstract: Computational Enzymology: Insight into Biological Catalyst from Modelling
in ChemInform
Van Der Kamp M
(2011)
"Lethal Synthesis" of Fluorocitrate by Citrate Synthase Explained through QM/MM Modeling
in Angewandte Chemie
Van Der Kamp M
(2017)
Dynamical origins of heat capacity changes in enzyme catalysed reactions
Van Den Berg B
(2016)
Structural basis for Mep2 ammonium transceptor activation by phosphorylation.
in Nature communications
Twidale RM
(2021)
Crystallography and QM/MM Simulations Identify Preferential Binding of Hydrolyzed Carbapenem and Penem Antibiotics to the L1 Metallo-ß-Lactamase in the Imine Form.
in Journal of chemical information and modeling
Twidale Rebecca M.
(2021)
Modelling the reactivity of zinc metalloenzymes and the SARS-CoV-2 main protease
| Description | EPSRC |
| Amount | £188,950 (GBP) |
| Funding ID | E/EP/G007705/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2013 |
| End | 03/2014 |
| Title | Sire 2007.1 |
| Description | 2007.1 (first official) release of the Sire molecular simulation framework. This included new methods developed to calculate QM/MM free energies. |
| Type Of Technology | Software |
| Year Produced | 2007 |
| Open Source License? | Yes |
| Impact | Sire is used in several pharmaceutical companies. This version of the code was used to run the simulations in "An efficient method for the calculation of quantum mechanics/molecular mechanics free energies" Christopher J. Woods, Frederick R. Manby and Adrian J. Mulholland J. Chem. Phys. 128 014109 (2008) doi:10.1063/1.2805379 The combination of quantum mechanics (QM) with molecular mechanics (MM) offers a route to improved accuracy in the study of biological systems, and there is now significant research effort being spent to develop QM/MM methods that can be applied to the calculation of relative free energies. Currently, the computational expense of the QM part of the calculation means that there is no single method that achieves both efficiency and rigor; either the QM/MM free energy method is rigorous and computationally expensive, or the method introduces efficiency-led assumptions that can lead to errors in the result, or a lack of generality of application. In this paper we demonstrate a combined approach to form a single, efficient, and, in principle, exact QM/MM free energy method. We demonstrate the application of this method by using it to explore the difference in hydration of water and methane. We demonstrate that it is possible to calculate highly converged QM/MM relative free energies at the MP2/aug-cc-pVDZ/OPLS level within just two days of computation, using commodity processors, and show how the method allows consistent, high-quality sampling of complex solvent configurational change, both when perturbing hydrophilic water into hydrophobic methane, and also when moving from a MM Hamiltonian to a QM/MM Hamiltonian. The results demonstrate the validity and power of this methodology, and raise important questions regarding the compatibility of MM and QM/MM forcefields, and offer a potential route to improved compatibility. |
| URL | http://www.siremol.org/Sire/Home.html |